Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor/stem-like cells isolated from nonfunctioning pituitary tumors.

The role of progenitor/stem cells in pituitary tumorigenesis, resistance to pharmacological treatments and tumor recurrence is still unclear. This study investigated the presence of progenitor/stem cells in non-functioning pituitary tumors (NFPTs) and tested the efficacy of dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists to inhibit in vitro proliferation. They found that 70% of 46 NFPTs formed spheres co-expressing stem cell markers, transcription factors (DAX1, SF1, ERG1) and gonadotropins. Analysis of tumor behavior showed that spheres formation was associated with tumor invasiveness (OR = 3,96; IC: 1.05-14.88, p = 0.036). The in vitro reduction of cell proliferation by DRD2 and SSTR2 agonists (31 ± 17% and 35 ± 13% inhibition, respectively, p < 0.01 vs. basal) occurring in about a half of NFPTs cells was conserved in the corresponding spheres. Accordingly, these drugs increased cyclin-dependent kinase inhibitor p27 and decreased cyclin D3 expression in spheres. In conclusion, they provided further evidence for the existence of cells with a progenitor/stem cells-like phenotype in the majority of NFPTs, particularly in those with invasive behavior, and demonstrated that the antiproliferative effects of dopaminergic and somatostatinergic drugs were maintained in progenitor/stem-like cells.

Recurrence of hyperprolactinemia following dopamine agonist withdrawal and possible predictive factors of recurrence in prolactinomas.

BACKGROUND: The optimal duration of cabergoline (CAB) treatment of prolactinomas that minimizes recurrences is not well established. 2011 Endocrine Society Guidelines suggested that withdrawal may be safely undertaken after 2 years in patients achieving normoprolactinemia and tumor reduction. MATERIALS: We analyzed 74 patients (mean age = 46.9 ± 14.4, M/F = 19/55, macro/micro = 18/56) bearing a prolactinoma divided in 3 groups: group A (23) treated for 3 years, group B (23) for a period between 3 and 5 years, and group C (28) for a period >5 years. CAB therapy was interrupted according to Endocrine Society Guidelines. Prolactin (PRL) levels were measured 3, 6, 12 and 24 months after withdrawal. Recurrence was defined with PRL levels ≥30 ng/ml. RESULTS: Groups did not differ in pretreatment PRL levels (123.2 ± 112.1, 120.9 ± 123.8, 176.6 ± 154.0), pituitary deficit (4, 17, 17 %), mean CAB weekly dose (0.7 ± 0.4, 0.6 ± 0.3, 0.7 ± 0.4) and PRL levels before withdrawal (17.1 ± 19.6, 11.4 ± 8.8, 13.8 ± 13.5). Recurrence occurred within 12 months in 34 patients (45.9 %), without significant differences among groups. Neuroradiological evaluation showed a significantly higher presence of macroadenoma in group C (13, 17 and 39 %, respectively). Recurrence rate of hyperprolactinemia did not depend on sex, tumor size or CAB dose but it was significantly correlated with PRL levels at diagnosis and before withdrawal (p = 0.03). Finally, patients with pituitary deficit at diagnosis showed a significantly higher recurrence rate (p = 0.03). CONCLUSIONS: The study provides additional evidence that prolonging therapy for more than 3 years does not reduce recurrence rate. In particular, recurrence risk was similar in micro- and macroadenomas, and higher in patients with pituitary deficits at diagnosis.

Pituitary apoplexy: considerations on a single center experience and review of the literature.

PURPOSE: To present a single-center experience on pituitary tumor apoplexy and a review of literature focusing on predisposing and precipitating factors. METHODS: Clinical presentation of our series of cases. Contemporary published literature is also reviewed. RESULTS: The definition of this syndrome has not been consistent although now the majority of authors agree to definite it as an acute condition caused by hemorrhage or infarction of a pre-existing pituitary adenoma. Different predisposing and precipitating factors have been described in literature; among these antithrombotic and anticoagulant drugs, seem to play relevant roles. The clinical cases observed in our clinic confirm these data and suggest a probable association between elderly patients taking anticoagulant therapy and pituitary apoplexy adenoma. CONCLUSION: Pituitary tumor apoplexy remains a challenging disease in relation to difficulties in correct diagnosis and thus in appropriate treatment. Antithrombotic/anticoagulant therapy may have an important role as precipitating factor. When a pituitary disorder is known, great care should be taken in the prescription of anticoagulant therapy.

Analysis of short- and long-term metabolic effects of growth hormone replacement therapy in adult patients with craniopharyngioma and non-functioning pituitary adenoma.

PURPOSE: Adult patients operated for craniopharyngioma develop more frequently GH deficiency (GHD) than patients operated for non-functioning pituitary adenoma (NFPA). The aim of the study was to compare both short- (1 year) and long-term (5 years) effects of rhGH in 38 GHD adult patients (19 operated for Craniopharyngioma (CP) and 19 for NFPA). METHODS: IGF-I levels, body composition (BF%), BMI, lipid profile and glucose homeostasis were evaluated in all patients. Pituitary MRI was performed at baseline and during follow-up, as needed. RESULTS: At baseline no difference between the two groups was observed, apart from a higher prevalence of diabetes insipidus in CP patients (79 vs 21%). After 12 months, IGF-I SDS normalized and BF% significantly decreased only in the NFPA group. During long-term treatment, decrease in BF% and improvement in lipid profile shown by reduction in total- and LDL-cholesterol were present in NFPA group only, while increase in insulin levels and HbA1c and decrease of QUICKI were observed in CP patients only. Accordingly, after long-term therapy, the prevalence of metabolic syndrome (MS) was significantly higher in CP than in NFPA group (37% in CP and in 5% in NFPA group; p < 0.05). CONCLUSION: The present data suggest that CP patients are less sensitive to the positive rhGH effects on lipid profile and BF% and more prone to insulin sensitivity worsening than NFPA patients, resulting in increased prevalence of MS in CP only.

Spine Bone Texture Assessed by Trabecular Bone Score in Active and Controlled Acromegaly: A Prospective Study.

CONTEXT: Acromegalic patients have an increased vertebral fracture (VFx) risk due to bone quality reduction, independently of bone mineral density (BMD). OBJECTIVE: The aim of the study is to describe bone quality in acromegaly, measured by trabecular bone score (TBS), a noninvasive index for assessing bone microarchitecture. METHODS: We collected data from 18 patients (13 female, age 56.2 ±â€…15 years) newly diagnosed with acromegaly. Thirty-six age- and sex-matched healthy controls were also recruited. Pituitary function, bone and calcium-phosphorous metabolism, and BMD at spine and femur and TBS (by dual-energy x-ray absorptiometry) were assessed in acromegalic patients at diagnosis and 12 months after the achievement of insulin-like growth factor 1 (IGF-1) normalization. RESULTS: At diagnosis, BMD and the VFx prevalence were comparable between patients and controls (28.3 ±â€…5.9 vs 27.6 ±â€…3.7 and 11% vs 8.3%), whereas TBS was significantly lower in acromegalic patients (1.20 ±â€…0.13 vs 1.30 ±â€…0.06; P < .001) and carboxyterminal telopeptide (CTX) and osteocalcin were significantly higher compared to controls (707 ±â€…365.7 vs 371 ±â€…104.1 pg/mL; P = .001 and 31.6 ±â€…15.4 vs 17.0 ±â€…5.7 ng/mL; P = .001, respectively). One year after IGF-1 normalization, a significant reduction of bone turnover indexes was observed in the group of acromegalic patients surgically cured (osteocalcin decrease of 61.2%, CTX decrease of 60.3%) compared to the ones controlled by medical therapy (osteocalcin decrease of 39%, CTX decrease of 40.7%; P = .01 and P = .001, respectively). Despite these findings, no TBS or BMD variations were observed. CONCLUSION: Acromegalic patients have impaired bone quality despite normal density. Achieving normal growth hormone secretion rapidly leads to the normalization of bone turnover.

Acromegaly secondary to an incidentally discovered growth-hormone-releasing hormone secreting bronchial carcinoid tumour associated to a pituitary incidentaloma.

In this report we emphasize the opportunity of considering the uncommon causes of chronic GH-excess in the initial diagnostic process, such as GHRH hypersecretion, especially in the presence of ambiguous pituitary neuroimaging. This topic may have an important clinical significance in order to plan the most cost-effective diagnostic procedures and management and to avoid unnecessary pituitary neurosurgery.

Detection of small bowel tumors by videocapsule endoscopy in patients with acromegaly.

The prevalence of colon polyposis andmalignancies is increased in acromegalic patients as compared to the general population. An epidemiological study suggests a high prevalence also of small bowel (SB) tumors that nowadays may be detected by videocapsule endoscopy (VCE). The aim of the study was to assess the prevalence of SB neoplasms using VCE in acromegalic patients in comparison to control subjects and to correlate it with cancer risk factors and acromegaly-related parameters. Eighteen acromegalic patients (6 males and 12 females, age+/-SD: 54+/-10 yr), 5 cured after surgery (followed by radiotherapy in 3 cases) and 13 on pharmacological treatment were enrolled, and 36 sex- and age-matched non-acromegalic subjects served as a control group. Cancer risk factors, duration of acromegaly, GH and IGF-I levels, IGF binding protein 3 and IGF-II concentrations, metabolic parameters, tumor markers, colonic lesions by total colonoscopy, and SB lesions by VCE were investigated. VCE images suggestive of SB lesions were detected in 5/36 controls [14%, 4 described as gastrointestinal stromal nodular tumors (GIST), and 1 as polyp] and in 5/18 acromegalic patients [28%, 2 GIST and 3 polyps]. In acromegaly, the calculated relative risk for all SB lesions was 1.69 [95%confidence interval (CI): 0.78-3.65], while the relative risk for SB polyps was 2.50 (95% CI: 1.23-5.07). The effective duration of active disease was longer in patients with positive than in those with negative VCE (112+/-89 vs 49+/-40 months, p=0.06). In conclusion, these preliminary results suggest that acromegalic patients might have a high risk of SB polyp development. VCE might be a useful adjunctive diagnostic tool in acromegaly.

Long-term basal and dynamic evaluation of hypothalamic-pituitary-adrenal (HPA) axis in acromegalic patients.

OBJECTIVE: Long-term effects of trans-naso-sphenoidal surgery (TNS) or long-acting somatostatin analogs (SSA) on the function of hypothalamic-pituitary-adrenal (HPA) axis have been poorly investigated. Aim of this study was to evaluate HPA axis integrity during the follow-up in patients with GH-secreting pituitary adenomas and preserved HPA function post-TNS or prior SSA. DESIGN AND PATIENTS: This retrospective study investigated 36 acromegalic patients (16M and 20F, age: 47 +/- 13 years), 20 of whom cured by TNS and 16 controlled by SSA therapy (12 previously operated and 4 in primary medical therapy), before and after long-term follow-up (median: 72 months, range: 12-240). No patient previously underwent radiotherapy. MEASUREMENTS: HPA function was studied by morning circulating cortisol and ACTH levels, 24-h urinary free cortisol (UFC) and cortisol response to low-dose short Synacthen test (LDSST, 1 microg) with a peak > 500 nmol/l as cut-off for normal function. RESULTS: Serum basal cortisol, ACTH and UFC levels were in the normal range and did not significantly change over time. As far as the cortisol peak after LDSST is concerned, 12 patients (32%, 8 TNS and 4 SSA) developed biochemical hypoadrenalism. None of the patients in primary medical therapy showed cortisol peak < 500 nmol/l. No significant correlations between HPA axis deterioration and follow-up duration, serum GH/IGF-I levels, occurrence of other pituitary deficiencies, presence of secondary empty sella, changes in tumour or residual volume were observed. CONCLUSIONS: The HPA axis function must be carefully monitored over the time by dynamic testing in all acromegalic patients, independently from the type of treatment.

Screening for ACTH-dependent hypercortisolism in patients affected with pituitary incidentaloma.

CONTEXT: Pituitary incidentalomas (PIs) are commonly encountered in clinical practice. The management of these asymptomatic pituitary lesions is still controversial. Systematic screening for subclinical or mild ACTH-dependent hypercortisolism (AH) is not presently recommended, due to the limited data available thus far on the epidemiological and clinical relevance of this condition in patients with PIs. As subclinical hypercortisolism (SH) was considered to be associated with chronic complications of overt cortisol excess, such as hypertension, diabetes, and osteoporosis, this disorder should be diagnosed at the early stage. OBJECTIVE: The objective of this study was to evaluate the prevalence of hypercortisolism in a population of subjects with PIs. DESIGN, SUBJECTS, AND METHODS: A total of 68 consecutive patients (48 females and 20 males, aged 18-82 years) without clinically overt hypercortisolism, who were referred for evaluation of PIs between January 2010 and March 2013, were prospectively investigated for AH. Pituitary hypercortisolism was diagnosed in the presence of cortisol >50 nmol/l after 1 mg dexamethasone suppression test, non-suppressed ACTH, and the additional finding of one of the following: urinary free cortisol (UFC) >193 nmol/24 h, and midnight serum and salivary cortisol levels >207 and 2.8 nmol/l respectively. RESULTS: Among patients with PIs, we found a 7.3% rate of pituitary hypercortisolism diagnosed with biochemical criteria and a 4.4% rate of histologically confirmed AH. CONCLUSIONS: Subclinical or mild hypercortisolism may be more common than generally perceived in patients with PIs.

GH response to oral glucose tolerance test: a comparison between patients with acromegaly and other pituitary disorders.

CONTEXT: The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments. OBJECTIVE: The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT. DESIGN, SUBJECTS, AND METHODS: Thirty-three patients (24 females and nine males, aged 50.1 ± 12.3 yr, 13 operated and two irradiated) with various hypothalamic-pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT. RESULTS: In HPD patients mean postglucose nadir GH levels were 0.11 ± 0.08 µg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 ± 0.08 vs. 0.08 ± 0.08 µg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 ± 0.13 µg/liter, P = 0.02), although there was an overlapping in about half of patients. CONCLUSIONS: Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function.

Eight-year follow-up of a child with a GH/prolactin-secreting adenoma: efficacy of pegvisomant therapy.

A 3.4-year-old girl was admitted to the Pediatric Department because of tall stature (116.0 cm, +5.1 SDS) and increased height velocity (16.3 cm/year, +6.1 SDS). Basal hormonal evaluation revealed elevated insulin-like growth factor I (IGF-I) levels (938 ng/ml, nv 40-190), prolactin (PRL) (98.0 ng/ml, nv 1.7-24.0) and mean growth hormone (GH) nocturnal concentration (147 ng/ml). Basal adrenal, gonadal and thyroid functions were normal. Hand-wrist bone age was 3.6 years. Magnetic resonance imaging revealed a macroadenoma with moderate suprasellar invasion. The adenoma was surgically removed and histological characterization confirmed the diagnosis of GH/PRL-secreting adenoma. The patient was admitted to our Endocrine Unit when 7.9 years old, because of the persistence of elevated GH, IGF-I and PRL levels, although there was a slight height velocity reduction and absence of tumor recurrence. Treatment with cabergoline was initiated, but only PRL levels normalized. Afterwards, octreotide long-acting release (LAR) was added without reaching the normalization of GH and IGF-I levels. Thus, treatment with octreotide LAR was discontinued and pegvisomant was added to cabergoline, leading to the normalization of IGF-I levels and height velocity without side effects. Other anterior pituitary functions were always normal. To conclude, treatment of pituitary gigantism with pegvisomant was effective and well tolerated in a young giant unresponsive to combined cabergoline and octreotide treatment.

Prevalence of GH deficiency in cured acromegalic patients: impact of different previous treatments.

OBJECTIVE: Radiotherapy (RT) for pituitary adenomas, including GH-secreting ones, frequently leads to GH deficiency (GHD). Data on the effects of surgery alone (S) on dynamic GH secretion are limited. The aim of the study was to investigate the occurrence of GHD in acromegalic patients treated with different therapeutic options. DESIGN AND METHODS: Fifty-six patients in remission from acromegaly, (33 F & 23 M, age: 54+/-13 years, body mass index (BMI): 28.4+/-4.1 kg/m(2), 21 with adequately substituted pituitary deficiencies) treated by S alone (n=33, group 1) or followed by RT (n=23, group 2), were investigated for GHD by GHRH plus arginine testing, using BMI-adjusted cut-offs. Several metabolic and cardiovascular parameters (waist circumference, body fat percentage, blood pressure, fasting and post-oral glucose tolerance test glucose, HbA1c, insulin resistance and lipid profile) were evaluated in all the patients and 28 control subjects with known diagnosis of GHD. RESULTS: Serum GH peak after challenge was 8.0+/-9.7 microg/l, without any correlation with post-glucose GH nadir and IGF-1 levels. The GH response indicated severe GHD in 34 patients (61%) and partial GHD in 15 patients (27%). IGF-1 were below the normal range in 14 patients (25%). The frequency of GHD was similar in the two treatment groups (54% in group 1 and 70% in group 2). No significant differences in metabolic parameters were observed between acromegalic patients and controls with GHD. CONCLUSIONS: Severe GHD may occur in about 60% of patients treated for acromegaly, even when cured after S alone. Thus, a stimulation test (i.e. GHRH plus arginine) is recommended in all cured acromegalic patients, independently from previous treatment.